PROJECT SUMMARY Despite modern antiretroviral therapy (ART), people living with HIV (PLWH) have an approximately 50% increased risk of cardiovascular disease. While persistent systemic inflammation appears to predict this risk, the optimal strategies to reduce inflammation and cardiovascular risk in treated HIV infection remain undefined. The overarching hypothesis of this proposal is that asymptomatic cytomegalovirus (CMV) replication is an important mediator of cardiovascular risk in treated HIV infection. This hypothesis is supported by the fact that CMV replicates in vascular endothelium and appears to play a role in atherosclerosis in immunocompromised solid-organ transplant recipients. Furthermore, over 90% of PLWH have asymptomatic CMV co-infection, CMV shedding levels are higher in treated PLWH than in the general population, surrogate markers of CMV are associated with vascular disease and myocardial infarction risk in treated HIV, and treating asymptomatic CMV replication in an earlier trial reduced the inflammatory pathways (i.e., sTNFR2) that most strongly predict vascular disease in treated HIV. Yet, no study has assessed whether treating asymptomatic CMV replication in treated PLWH reduces vascular inflammation and markers of endothelial dysfunction. Our proposal addresses these issues by leveraging a separately funded placebo-controlled clinical trial led by Dr. Hunt of the novel CMV terminase inhibitor letermovir in 180 ART-suppressed PLWH in the ACTG (A5383). Aim 1 will determine whether 48 weeks of letermovir reduces vascular inflammation as assessed by FDG-PET/CT in a subset of 92 participants. Aim 2 will assess whether letermovir reduces plasma markers of endothelial dysfunction and Aim 3 will characterize the plasma proteomic signatures that are altered by letermovir therapy using a modified aptamer assay and relate these changes to concurrent changes in vascular inflammation. These studies also benefit from a strong MPI team with complementary expertise and a long history of collaboration including Drs. Hunt (HIV immunopathogenesis, clinical trials), Tawakol (cardiology, FDG-PET/CT imaging), and Hsue (HIV cardiology, clinical trials); a team of co-Is with proteomics and bioinformatics expertise (Drs. Ganz and Olshen); and the largest HIV therapeutics clinical trials network in the world (ACTG). Collectively, these studies will test for the first time treated HIV infection ? and more broadly in humans - a potential causal role of asymptomatic CMV replication in vascular disease in the context of a rigorously designed clinical trial. If successful, this study could help motivate a future Phase 3 trial of letermovir to reduce cardiovascular events among other complications in treated HIV infection.